The compound phenylthiobutyl-isoquinoline of the formula 
and its preparation starting from L-serine is described, e.g., in U.S. Pat. No. 5,484,926, incorporated herein by reference. This compound is a valuable intermediate for the manufacture of pharmacologically active compounds, suitable for the treatment of viral infections, especially those caused by HIV and other retroviruses, described in U.S. Pat. No. 5,484,926, e.g., at columns 16 and 17, such as represented by formula 
wherein Ph is phenyl,
and pharmaceutically acceptable salts thereof.
The present invention relates to a new method for making compounds of formula 
and intermediates for making compounds of formula II.
The compounds of this invention are useful intermediates for the manufacture of pharmacologically active compounds suitable for the treatment of viral infections, particularly, those caused by HIV and other retroviruses.
The method of the present invention is characterized by less reaction steps, more convenient reaction conditions and a higher overall yield of the desired stereoisomer of formula II. Particularly, in accordance with the method of the present invention, protection of a carbamate group of an intermediate phenylthio compound by a silyl group leads to a considerable increase in yield compared to that of prior methods for making compounds of formula II.
The method of the present invention comprises
(a) reacting diprotected L-serine of formula 
xe2x80x83wherein R is lower alkyl and R1 is lower alkyl or benzyl,
with mesyl or tosyl chloride and a thiophenolate;
(b) reacting the resulting phenylthio compound of formula 
with halogenated methyllithium;
(c) reducing a resulting halogen ketone of formula 
xe2x80x83wherein X is halogen,
to the corresponding halogen alcohol of formula 
(d) treating the halogen alcohol of formula V with a base to form the [(R)-1-[(S)-oxiran-2-yl]-2-phenylthio-ethyl]-carbamic acid ester of formula 
(e) reacting the carbamic acid ester of formula IV with N-tert.-butyl-decahydro-(4aS, 8aS)-isoquinoline-3(S)-carboxamide of formula
xe2x80x83and
(f) treating the resulting compound of formula 
with a base to yield the compound of formula II above.
The term xe2x80x9clower-alkylxe2x80x9d used throughout the specification and claims refers to straight- or branched-chain saturated hydrocarbon residues with 1-6, preferably 1-4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, a pentyl or a hexyl group with methyl and ethyl being preferred, especially for R1. Especially preferred in connection with the present invention are compounds wherein R1 is methyl. Halogen denotes chlorine, bromine and iodine with chlorine being preferred.
The starting diprotected L-serines of formula VIII are known compounds and can easily be prepared from L-serine via reacting the corresponding L-serine lower alkyl esters with the corresponding chloroformates.
The phenylthio compounds of formula VII may be prepared using methods known in the art (e.g. Sasaki et al., Tetrahedron Letters 28, 6069 (1987)). The amino- and carboxy-protected L-serine is transformed into its tosylate or mesylate in the presence of an amine such as pyridine or triethylamine in an aprotic solvent such as methylene chloride or acetic acid ester and then reacted with a thiophenolate. The thiophenolate can be prepared in situ from thiophenol and a strong base, at low temperature, preferably a temperature from xe2x88x9210xc2x0 C. up to 0xc2x0 C..
Any conventional halomethylating agent can be used to halomethylate the phenylthio compounds of formula VII to form the halogen ketone compounds of formula VI. The halomethylation of the resulting phenylthio compound VII is preferably effected using halogenated methyllithium which is generated in situ. The latter is conveniently formed using dihalogenated methane, e.g., dichloro-, dibromo- or diiodomethane, preferably using bromochloromethane, and a lower-alkyl-lithium, such as, for example, butyllithium or hexyllithium, in an ether, preferably tetrahydrofuran, at xe2x88x9220xc2x0 to xe2x88x92120xc2x0 C., preferably xe2x88x9280xc2x0 C.
In accordance with the method of the present invention, the halomethylation of the phenylthio compound VII to the halogen ketone VI is carried out by
(a) silylating a carbamate group of a compound of formula VII in the presence of a lower-alkyl-lithium to form a silyl-protected compound; and
(b) alkylating the silyl-protected compound in the presence of dihalogenated methane with a lower-alkyl-lithium to produce a halogen ketone of formula VI.
Preferred silyl-protected compounds of the present invention include compounds of the
general formula VII-A and/or VII-B formed as an intermediate 
In accordance with the present invention, any conventional method for producing the silyl-protected compounds of formulas VII-A and VII-B can be used. Suitable silylating agents for use with the present invention include organochlorosilanes of the formula ClSi(R2, R3, R4), wherein R2, R3 and R4 are lower-alkyl or phenyl. A preferred organochlorosilane is chlorotrimethylsilane.
The method of the present invention for making the halogen ketone of formula VI provides new and unexpected results. Surprisingly, the protection of the carbamate group present in compound VII by a silyl group yielding compounds VII-A and/or VII-B as intermediates leads to a considerable increase in yield of the halogen ketone compounds of formula VI. Furthermore, this novel method for producing the halogen ketone compounds of formula VI can be used in a process for making the compounds of formula II to provide increased yields of the compounds of formula II compared to prior methods.
In accordance with the present invention, any conventional means can be used to alkylate the silyl-protected compounds of formula VII-A and VII-B. Preferred alkylating agents are lower-alkyl-lithium compounds such as butyllithium or hexyllithium. Moreover, an almost complete halomethylation of the phenylthio compounds of formula VII can be achieved using significantly less lower-alkyl-lithium and dihalogenated methane compared to amounts typically used in conventional halomethylation methods. In accordance with the present invention, the halogen ketone VI can be reduced to the corresponding alcohol of formula V with a hydride In a solvent such as toluene, tetrahydrofuran or an alcohol, preferably methanol, ethanol or isopropanol, at a temperature between xe2x88x9230 and 80xc2x0 C., preferably between xe2x88x9215xc2x0 C. and 50xc2x0 C., optionally under reduced pressure, using sodium bis-(2-methoxy-ethoxy)-aluminium hydride, lithium aluminium hydride, lithium aluminium tri-tert.-butoxyhydride, sodium borohydride, tetramethylammonium borohydride or, preferably, using, an aluminium tri-alkoxide or lithium aluminium tri-alkoxyhydride. The term xe2x80x9calkoxidexe2x80x9d means lower alkoxy with the lower-alkyl residue being as defined above, such as, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, or isobutoxy, tert.-butoxy, as well as pentyloxy or hexyloxy groups. The aluminium compounds can have identical or different alkoxy groups. Aluminium tri-isopropoxide and aluminium tri-sec.-butoxide are especially preferred compounds. The reagents lithium aluminium tri-tert.-butoxyhydride, aluminium tri-isopropoxide and aluminium tri-sec.-butoxide gave unexpected high stereoselectivity in a molar ratio of at least 9:1 of the (1S,2S) and (1S, 2R) isomeric halohydrins V, which could be crystallized in  greater than 99% optical purity and with high yield.
The ring closure of the halohydrin of formula V to form the corresponding epoxide of formula IV can be carried out by conventional means, such as in a solvent, for example, ethanol or preferably, a toluene/water mixture in the presence of a base such as an alkaline or alkaline earth metal hydroxide, preferably sodium or potassium hydroxide, at a temperature between 0xc2x0 and 80xc2x0 C., preferably 40-50xc2x0 C. The epoxide which is formed need not be purified.
The reaction of the epoxide of formula IV with the isoquinoline X to form compound III can be carried out by any conventional means, such as, in a solvent, for example, a hydrocarbon, such as toluene, or a lower-alkanol, preferably ethanol, while heating under reflux, at preferably 20-100xc2x0 C., and most preferably 80xc2x0 C.
The cleavage of the N-protecting group from the compound of formula III can be carried out by any conventional means such as, in a solvent, for example, water, ethanol or a mixture thereof, using a base such as sodium or potassium hydroxide while heating to the reflux temperature, preferably 20-100xc2x0 C., especially 80xc2x0 C.
A further aspect of the present invention is the new intermediate compounds of formulas VII, VI, V, IV and III wherein R1 is lower alkyl, namely, compounds of formulas VII-1, VI-1, V-1, IV-1 and III-1, as well as the use of these new intermediate compounds for the preparation of the compound of formula II or pharmacologically active compounds suitable for treating viral infections, such as the compound of formula I and their salts mentioned above. A preferred embodiment of the new compounds of this invention are those wherein R1 is C1-3 alkyl, especially methyl or ethyl.
Especially preferred compounds of formulas III, IV, V, VI and VII are those wherein R and R1 are methyl and X is chlorine, such as
methyl (1R, 2R)-[1-phenylthiomethyl-3-[(3S, 4aS, 8aS)-3-tert.-butoxycarbamoyl-decahydroisoquinol-2-yl]-2-hydroxypropyl]-carbamate;
methyl [(R)-1-[(S)-oxiran-2-yl]-2-phenylthio-ethyl]-carbamate;
methyl (1R, 2S)-[3-chloro-2-hydroxy-1-(phenylthiomethyl)-propyl]-carbamate;
methyl [3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and methyl (3-phenylthio-(R)-2-methoxycarbonylamino)-propionate.
Finally, the compounds of formulas II, III, IV, V, VI and VII, when obtained by the method described hereinbefore or in the following Examples, are a further aspect of the present invention.
A compound of formula I can be obtained, e.g., in accordance with the method described in Example 23 of U.S. Pat. No. 5,484,926, using 70 mg of the compound of formula II, 24.6 mg of 3-hydroxy-2-methylbenzoic acid, 33 mg of DDC and 22 mg of HOBTxc2x7H2O in 4 ml of THF.
The formation of pharmaceutically acceptable salts can be performed by conventional methods known in the art. The methanesulfonic acid salt, e.g., can be prepared as described in Example 75 of U.S. Pat. No. 5,484,926 by dissolving 3.34 g of compound I in 30 ml of MeOH and 30 ml of methylene chloride and adding a solution of 596 mg of methanesulfonic acid in 10 ml of methylene chloride dropwise and working up of the reaction mixture to obtain the desired compound in pure form.
Reaction Scheme I summarizes the preferred reaction steps for the preparation of compounds VIII to I wherein R and R1 are methyl and X is chlorine, This reaction scheme is described in more detail in the examples of the specification. 
The following Examples illustrate the present invention in more detail without limiting it.